Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial

Schwab, Claire, Cranston, Ruth E., Ryan, Sarra L., Butler, Ellie, Winterman, Emily, Hawking, Zoe, Bashton, Matthew, Enshaei, Amir, Russell, Lisa J., Kingsbury, Zoya, Peden, John F., Barretta, Emilio, Murray, James, Gibson, Jude, Hinchliffe, Andrew C., Bain, Robert, Vora, Ajay, Bentley, David R., Ross, Mark T., Moorman, Anthony V. and Harrison, Christine J. (2023) Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial. Leukemia, 37 (3). pp. 529-538. ISSN 0887-6924 (In Press)

Preview	Text (Advance online version) s41375-022-01799-4.pdf - Published Version Available under License Creative Commons Attribution 4.0. Download (2MB) | Preview
Preview	Text (Final published version) s41375-022-01799-4.pdf - Published Version Available under License Creative Commons Attribution 4.0. Download (2MB) | Preview

Abstract

Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.

Actions (login required)

View Item

Downloads